Assuntos
Neoplasias da Mama , Injeções Espinhais , Neoplasias Meníngeas , Metotrexato , Tiotepa , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Metotrexato/administração & dosagem , Tiotepa/administração & dosagem , Neoplasias Meníngeas/secundário , Neoplasias Meníngeas/tratamento farmacológico , Carcinomatose Meníngea/tratamento farmacológico , Carcinomatose Meníngea/secundárioRESUMO
Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY + TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA. We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate P-value < .2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses. A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3) and 7.2% (95% CI, 2.9-11.5) in allogeneic and autologous HCTs, respectively (P = .62). In allogeneic recipients (n = 417), the 1-year cumulative incidence of TA-TMA with CY + TT as part of conditioning was 35.7% (95% CI, 15.7-55.7) compared to 11.7% (95% CI, 7.2-16.2) with either CY or TT alone, and 1.2% (95% CI, 0-2.8) if neither agent was included in the conditioning regimen (P < .001). Use of either CY or TT (HR = 10.14; P = .002) or CY + TT (HR = 35.93; P < .001), viral infections (HR = 4.3; P = .017) and fungal infections (HR = 2.98; P = 0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n = 141), the 1-year cumulative incidence of TA-TMA with CY + TT was 19.6% (95% CI, 8.8-30.6) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (P < .001). TA-TMA occurred only in patients with neuroblastoma receiving CY + TT as part of their conditioning. For autologous patients who received CY + TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7) compared to 38.1% (95% CI, 35-41.2) for those CMV seropositive (P = .007). These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY + TT should be considered whenever possible to limit the development of TA-TMA.
Assuntos
Ciclofosfamida , Transplante de Células-Tronco Hematopoéticas , Tiotepa , Microangiopatias Trombóticas , Condicionamento Pré-Transplante , Humanos , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Estudos Retrospectivos , Adolescente , Criança , Adulto Jovem , Condicionamento Pré-Transplante/efeitos adversos , Pré-Escolar , Adulto , Fatores de Risco , LactenteRESUMO
Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.
Assuntos
Neoplasias do Sistema Nervoso Central , Injeções Espinhais , Tiotepa , Humanos , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/secundário , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/secundárioRESUMO
Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tiotepa , Condicionamento Pré-Transplante , Irradiação Corporal Total , Humanos , Irradiação Corporal Total/métodos , Condicionamento Pré-Transplante/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Bussulfano/uso terapêutico , Bussulfano/administração & dosagem , Adulto , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico , Feminino , Masculino , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Adolescente , Adulto Jovem , Transplante Homólogo/métodosRESUMO
BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.
Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Humanos , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Bussulfano/farmacocinética , Bussulfano/administração & dosagem , Condicionamento Pré-Transplante/métodos , Masculino , Transplante de Células-Tronco Hematopoéticas/métodos , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Resultado do Tratamento , Estudos Retrospectivos , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Vidarabina/administração & dosagem , Tiotepa/uso terapêutico , Tiotepa/administração & dosagem , Tiotepa/farmacocinética , Intervalo Livre de Doença , Seguimentos , Doenças Hematológicas/terapia , Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/administração & dosagemRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.
Assuntos
Bussulfano , Células Dendríticas , Transplante de Células-Tronco Hematopoéticas , Tiotepa , Condicionamento Pré-Transplante , Vidarabina , Humanos , Vidarabina/análogos & derivados , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico , Condicionamento Pré-Transplante/métodos , Células Dendríticas/patologia , Tiotepa/administração & dosagem , Tiotepa/uso terapêutico , Masculino , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/patologia , Feminino , Transplante Homólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , AloenxertosRESUMO
ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.
Assuntos
Bussulfano , Leucemia Mieloide Aguda , Sulfonamidas , Vidarabina/análogos & derivados , Humanos , Bussulfano/farmacologia , Tiotepa/uso terapêutico , Cladribina/farmacologia , Leucemia Mieloide Aguda/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Combinação de Medicamentos , Linhagem Celular Tumoral , ApoptoseRESUMO
ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.
Assuntos
Anemia Falciforme , Transplante de Medula Óssea , Doença Enxerto-Hospedeiro , Transplante Haploidêntico , Humanos , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/efeitos adversos , Masculino , Feminino , Criança , Adolescente , Adulto , Anemia Falciforme/terapia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante Haploidêntico/métodos , Pré-Escolar , Adulto Jovem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/administração & dosagem , Condicionamento Pré-Transplante/métodos , Pessoa de Meia-Idade , Tiotepa/administração & dosagem , Tiotepa/uso terapêuticoRESUMO
Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma , Humanos , Tiotepa/uso terapêutico , Bussulfano/uso terapêutico , Metotrexato/uso terapêutico , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma/terapia , Sistema Nervoso Central , Terapia Combinada , Transplante de Células-Tronco , Condicionamento Pré-TransplanteRESUMO
A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk ß-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with ß-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mgâ¢h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mgâ¢hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mgâ¢h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Talassemia beta , Humanos , Talassemia beta/terapia , Bussulfano/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Tiotepa , Condicionamento Pré-Transplante/métodos , Doença Enxerto-Hospedeiro/induzido quimicamente , Doença Enxerto-Hospedeiro/tratamento farmacológicoRESUMO
ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.
Assuntos
Bussulfano , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Pré-Escolar , Humanos , Bussulfano/análogos & derivados , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Recidiva , Tiotepa/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Organ dysfunction, including pulmonary function impairment, plays a key role in the choice of conditioning chemotherapy before autologous hematopoietic stem cell transplantation (auto-HSCT). Replacement of BCNU/carmustine as part of BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) conditioning protocol by thiotepa (TEAM) reduces pulmonary toxicity while maintaining efficacy. We retrospectively analyzed the association of clinical characteristics, comorbidities, and organ function with outcomes after conditioning with BEAM or TEAM. Three hundred ninety-six patients undergoing auto-HSCT (n = 333 with BEAM; n = 63 with TEAM) at our institution between 2008 and 2021 were included in this study. In the multivariate analysis, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, progressive disease (PD) before auto-HSCT, Karnofsky performance score (KPS) ≤ 80%, HCT-CI score ≥ 4, and cardiac disease before auto-HSCT were associated with decreased overall survival (OS) in patients treated with BEAM. In contrast, only PD before auto-HSCT was identified in patients treated with TEAM. Patients conditioned with BEAM and DLCOcSB ≤ 60% had higher non-relapse mortality, including pulmonary cause of death. In summary, we have identified clinical and pulmonary risk factors associated with worse outcomes in patients conditioned with BEAM compared to TEAM. Our data suggest TEAM conditioning as a valid alternative for patients with comorbidities, including pulmonary dysfunction and/or poorer performance scores, before auto-HSCT.
Assuntos
Carmustina , Transplante de Células-Tronco Hematopoéticas , Humanos , Carmustina/efeitos adversos , Tiotepa , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo , Citarabina/efeitos adversos , Etoposídeo/uso terapêutico , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Melfalan/efeitos adversosRESUMO
Total body irradiation (TBI) at myeloablative doses is superior to chemotherapy-based regimens in young patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, in elderly and unfit patients, in whom reduced-intensity conditioning (RIC) regimens are preferred, whether a TBI-based or a chemotherapy-based approach is better is unexplored. Thiotepa can be used as part of ALL conditioning regimens. The current study aimed to compare transplantation outcomes after RIC with TBI-based or thiotepa-based regimens in patients with ALL. The study cohort comprised patients aged ≥40 years undergoing allo-HSCT for ALL in first complete remission between 2000 and 2020 who received an RIC regimen containing either TBI (4 to 6 Gy) or thiotepa. We identified a total of 265 patients, including 117 who received a TBI-based RIC regimen and 148 who received a thiotepa-based RIC regimen. Univariate analysis revealed no significant differences in the following transplantation outcomes for TBI versus thiotepa: relapse, 23% versus 28% (P = .24); nonrelapse mortality, 20% versus 26% (P = .61); leukemia-free survival, 57% versus 46% (P = .12); overall survival, 67% versus 56% (P = .18); graft-versus-host disease (GVHD]/relapse-free survival, 45% versus 38% (P = .21); grade II-IV acute GVHD, 30% in both groups (P = .84); grade III-IV acute GVHD, 9% versus 10% (P = .89). The sole exception was the incidence of chronic GVHD, which was higher in the recipients of TBI-based regimens (43% versus 29%; P = .03). However, multivariate analysis revealed no differences in transplantation outcomes between the 2 groups. In patients aged ≥40 years receiving RIC, use of a thiotepa-based regimen may represent a valid alternative to TBI-based regimens, as no differences were observed in the main transplantation outcomes.
Assuntos
Doença Enxerto-Hospedeiro , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Idoso , Humanos , Tiotepa/uso terapêutico , Estudos Retrospectivos , Irradiação Corporal Total/efeitos adversos , Medula Óssea , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Doença Aguda , Doença Enxerto-Hospedeiro/prevenção & controleRESUMO
Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P = .1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P = .24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P = .5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P = .039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P = .002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin , Adulto , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Análise de Sobrevida , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Bussulfano/uso terapêutico , TiotepaRESUMO
AIM: Chronic graft versus host disease (cGVHD) is a major cause of morbidity postallogeneic peripheral blood stem cell transplant (PBSCT). There is paucity of literature describing incidence, risk factors, characteristics, and outcome of cGVHD in children undergoing haploidentical PBSCT with post-transplant cyclophosphamide (PTCy). Here, we describe our experience from our center regarding the same. METHODS: All children who underwent haploidentical PBSCT with PTCy between January 2016 and December 2021 at our center and survived beyond day+100 post-transplant were included in this retrospective study. Conditioning regimens used were: Thiotepa-Fludarabine-Cyclophosphamide with 2 Gy single fraction total body irradiation, Thiotepa-Busulfan-Fludarabine, Fludarabine-total body irradiation and Fludarabine-Melphalan. Peripheral blood was used as stem cell source in all patients. GVHD prophylaxis was PTCy 50 mg/kg on day +3 and +4, Mycophenolate mofetil and Calcineurin inhibitors. Clinical and laboratory data was electronically retrieved and analyzed based on National Institute of Health Consensus Criteria-2014 at regular intervals. Impact of various patient, donor, and transplant-related factors on development of cGVHD were analyzed. Incidence of relapse, event free survival (EFS) and overall survival (OS) were calculated and compared between cGVHD and no cGVHD groups. Patients with rejection were excluded from risk factor analysis for cGVHD but were considered for survival analysis. RESULTS: Fifty-one children included in this study. Median age of transplant of our cohort was 7.5 years with male:female=1.6:1. Eight patients had rejection with autologous recovery. History of acute GVHD (aGVHD) was present in 15/51 (Grade III to IV in 7/51). cGVHD developed in 19/51 patients (mild-9/51, moderate-6/51, and severe-4/51). Skin was the most common organ involved (100%) followed by gastrointestinal tract (47.4%), liver (36.8%), eyes (21%), lungs (21%), mouth (15.7%), and joints (5.2%). Advanced donor age (>30 y) and previous aGVHD were found to be significantly associated with increased risk of developing cGVHD. At last follow-up, complete response and partial response of cGVHD was seen in 6/19 and 4/19 patients, respectively. Overall mortality was 15/51 (cause of mortality was relapse of cancer 8/15, cGVHD-3/15, other 4/15). EFS and OS of full cohort was 55% and 70.6%, respectively. Compared with patients without cGVHD, patients with cGVHD demonstrated a lower relapse (18.2% vs. 40%, P =0.2333), higher EFS (68.4% vs. 53.1%, P =0.283), and higher OS (73.7% vs. 68.8%, P =0.708). CONCLUSION: Incidence of cGVHD was high in children undergoing haploidentical PBSCT with PTCy. Other than PBSC graft source; donor age and previous aGVHD were the risks factors for development of cGVHD. Patients with cGVHD had lower incidence of relapse translating into better survival but this difference was not statistically significant.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco de Sangue Periférico , Criança , Humanos , Masculino , Feminino , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos Retrospectivos , Incidência , Tiotepa/uso terapêutico , Ciclofosfamida/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fatores de Risco , Recidiva , Condicionamento Pré-Transplante/efeitos adversosRESUMO
Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2 (FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n = 1002; FBM/FTM, n = 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p < 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p = 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p = 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p = 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p = 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Vidarabina/análogos & derivados , Humanos , Adulto , Melfalan/farmacologia , Melfalan/uso terapêutico , Carmustina , Tiotepa/farmacologia , Tiotepa/uso terapêutico , Bussulfano , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Recidiva , Resposta Patológica Completa , Transplante de Células-Tronco Hematopoéticas/métodos , Doença Enxerto-Hospedeiro/etiologia , Alquilantes , Estudos RetrospectivosAssuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Vinorelbina , Tiotepa/uso terapêutico , Estudos Retrospectivos , Vimblastina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metástase Neoplásica , Resultado do TratamentoRESUMO
Secondary central nervous system (CNS) lymphoma (SCNSL) is a rare but clinically challenging scenario with historically disappointing outcomes. SCNSL refers to lymphoma that has spread into the CNS concurrently with systemic disease or CNS relapse during or after frontline immunochemotherapy, presenting with or without systemic lymphoma. Diffuse large B-cell lymphoma (DLBCL) denotes the most common entity, but an increased incidence is observed in other histologies, such as Burkitt lymphoma and mantle-cell lymphoma. The incidence, timing in disease course, location, evidence supporting the use of CNS prophylaxis, and treatment pathways vary according to histology. No randomized data exist to delineate the best treatment approaches with current recommendations based on retrospective and single-arm studies. However, a regimen comprising immunochemotherapy, incorporating agents that cross the blood-brain barrier, followed by thiotepa-containing conditioning and autologous stem-cell transplant outlined in the international MARIETTA study demonstrated improvement in outcomes, representing a major accomplishment in the care of patients with DLBCL with SCNSL. Anti-CD19 chimeric antigen receptor T cell denotes a paradigm shift in the treatment of patients with systemic aggressive lymphomas, with emerging data also demonstrating efficacy without higher neurotoxicity in those with SCNSL. In this manuscript we discuss 5 clinical scenarios and review the evidence supporting our recommendations.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Humanos , Adulto , Estudos Retrospectivos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Tiotepa/uso terapêutico , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration [HR] = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients.